UC San Francisco - Arthritishttps://www.ucsf.edu/topics/arthritis
enQMRI Sees Cartilage Damage Before It’s Too Latehttps://www.ucsf.edu/news/2016/11/404791/qmri-sees-cartilage-damage-its-too-late
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<a href="/bio/nina-bai">Nina Bai</a> </div>
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UCSF-Developed Technology is Now Helping Clinicians Detect Early Signs of Osteoarthritis </h2>
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<figure class="image image-2014_wysiwyg_full"><img alt="a qMRI image of a knee joint shows healthy cartilage as blue as unhealthy as red" height="433" src="/sites/default/files/styles/2014_wysiwyg_full/public/fields/field_insert_file/news/qmri-knee-joint.jpg?itok=pZ_cGnDQ" width="770" /><figcaption>A qMRI image of a knee joint shows areas of healthy cartilage in blue and degenerating cartilage in red.</figcaption></figure> </div>
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<p>One in 20 adults suffers from osteoarthritis, caused by wear and tear of the joints. But early signs of the disease – subtle biochemical changes to the cartilage – are invisible to most current clinical imaging techniques, and patients often remain undiagnosed until the damage is irreparable.</p>
<p>Researchers at UC San Francisco’s <a href="https://radiology.ucsf.edu/research/labs/musculoskeletal-quantitative-imaging" target="_blank">Musculoskeletal Quantitative Imaging Research Interest Group</a> (MQIR) are pioneering a new technique, known as quantitative magnetic resonance imaging, or qMRI, that can reveal the earliest signs of cartilage damage.</p>
<p><a href="http://profiles.ucsf.edu/sharmila.majumdar" target="_blank">Sharmila Majumdar</a>, PhD, director of MQIR, has been advancing qMRI techniques for more than a decade and is now working to optimize and translate qMRI for clinical applications.</p>
<p>For the last four years, Majumdar’s group has made the technology available to UCSF clinicians, and UCSF is one of only two medical centers in the world where clinicians are now using qMRI to study and develop preventive therapies for osteoarthritis.</p>
<h3>Quantifying Cartilage Composition</h3>
<p>On an X-ray, degenerating cartilage can only be inferred by studying the space between bones. Standard MRI provides only the morphology of cartilage, and by the time large lesions are visible, the damage is irreversible. QMRI is the only way to provide a detailed assessment of early cartilage degeneration.</p>
<p>Like standard MRI, qMRI uses magnetic fields and sequences of radiofrequency pulses to measure changes in the hydrogen atoms in our bodies – different tissues produce different signals. But while standard MRI produces essentially qualitative images that then must be interpreted by a radiologist, qMRI uses specialized programming to extract quantifiable values out of the image itself.</p>
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<p class="wysiwyg_quote--content">QMRI allows you to look at cartilage in a healthy enough stage when you can still reverse the damage. That opens up a whole world of interventions.</p>
<p class="wysiwyg_quote--author">Richard Souza, PhD, PT</p>
<p class="wysiwyg_quote--org">Associate Professor of Physical Therapy</p>
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<p>These values are then translated into color scale – producing full color, information-rich images, with red indicating areas of degenerating cartilage.</p>
<p>The technology can detect the early signs of disease in cartilage, including decreased proteoglycan content, increased water content and weakening of the collagen matrix.</p>
<p>“It’s extremely valuable to be able to quantify cartilage composition, because subtle composition changes are reversible,” said <a href="http://profiles.ucsf.edu/richard.souza" target="_blank">Richard Souza</a>, PhD, PT, associate professor of physical therapy. “QMRI allows you to look at cartilage in a healthy enough stage when you can still reverse the damage. That opens up a whole world of interventions.”</p>
<p>Early biochemical changes to cartilage can be healed by reducing stress to the joints through physical therapy or surgery.</p>
<p>As a physical therapist with a background in biomechanics, Souza uses qMRI combined with motion analysis technology to monitor how specific movements, a particular bending of the knee, for example, may exacerbate osteoarthritis. He can help people modify the way they walk and exercise to avoid further damage to the joints.</p>
<h3>Early Interventions may Prevent Joint Replacement</h3>
<p><a href="http://profiles.ucsf.edu/alan.zhang" target="_blank">Alan Zhang</a>, MD, assistant professor of orthopaedic surgery, sees many young athletes who come in with hip joint pain. He uses qMRI to see if they have early cartilage injury and may recommend surgery to repair tears or remove bone abnormalities to reduce further damage.</p>
<figure class="image image-2014_inline_5-col" style="float:left"><img alt="A qMRI image of hip joints shows cartilage damage in red" height="306" src="/sites/default/files/styles/2014_inline_5-col/public/fields/field_insert_file/news/qmri-hip-joint.jpg?itok=i2A0-9W6" width="470" /><figcaption>Clinicians like Alan Zhang, MD, can use qMRI of hip joints to detect early cartilage injury and plan surgical interventions.</figcaption></figure><p>“We’re using qMRI to assess early cartilage injury caused by abnormal boney impingement lesions that may be especially common in the hip,” Zhang said. “Then we may plan surgical interventions to re-contour these lesions or repair certain tears with the goal to prevent the injuries from getting worse.”</p>
<p>Zhang’s clinical research aims to show that these early, minimally invasive interventions can prevent the need for complete joint replacement later on.</p>
<p>QMRI currently is limited to the knee and hip joints, but researchers are working to expand the technique to other joints, such as the ankle and the shoulder, each of which have different surfaces and require different acquisition methods.</p>
<p>Majumdar hopes to speed up data analysis so that images are ready as soon as the patients are out of the scanner. She and <a href="http://profiles.ucsf.edu/valentina.pedoia" target="_blank">Valentina Pedoia</a>, PhD, associate specialist in radiology, are also exploring the possibility of incorporating machine learning methods to allow qMRI to identify patients at risk for joint replacement or those likely to respond to particular interventions.</p>
<p>“In the last 10 years we’ve seen tremendous improvement in imaging equipment and computational resources – but we’re not done,” Majumdar said. </p>
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Fri, 04 Nov 2016 17:45:00 +0000nina.bai404791 at https://www.ucsf.eduhttps://www.ucsf.edu/news/2016/11/404791/qmri-sees-cartilage-damage-its-too-late#commentsUCSF Helps Develop Unified Classification Criteria for Sjogren’s Syndromehttps://www.ucsf.edu/news/2016/11/404766/ucsf-helps-develop-unified-classification-criteria-sjogrens-syndrome
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Tue, 01 Nov 2016 18:15:00 +0000mbillings404766 at https://www.ucsf.eduhttps://www.ucsf.edu/news/2016/11/404766/ucsf-helps-develop-unified-classification-criteria-sjogrens-syndrome#commentsBold Innovation Program Fast-Tracks Precision Medicine Researchhttps://www.ucsf.edu/news/2016/04/402541/bold-innovation-program-fast-tracks-precision-medicine-research
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Carol Pott </div>
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<p><img alt="A stock image shows a pipette tip filling in an eppendorf tube" class="image-2014_inline_5-col" height="264" src="/sites/default/files/styles/2014_inline_5-col/public/fields/field_insert_file/news/Precision-Medicine-Marcus-Program.jpg?itok=kX9jsFv6" style="float:right" width="470" />Imagine a world in which a single human cell can be separated from a tumor and dissected to see each individual cancer-causing genetic mutation. Imagine a physician-scientist using that information to precisely individualize the most effective treatment for a specific cancer. These exciting advances in medicine and health are being researched in projects recently funded by the <a href="http://rdo.ucsf.edu/news/marcus-program-precision-medicine-innovation" target="_blank">George and Judy Marcus Program in Precision Medicine Innovation</a>.</p>
<p>One of the projects, developed by <a href="http://profiles.ucsf.edu/trever.bivona" target="_blank">Trever Bivona</a>, MD, PhD, and <a href="http://profiles.ucsf.edu/james.fraser" target="_blank">James Fraser</a>, PhD, looks at precisely treating disease-driving genetic mutations and may eventually produce a method of activating or inhibiting explicit mutations in proteins. If their project is successful, a whole new class of drug therapies could be developed to activate or inhibit specific proteins that cause cancerous mutations.</p>
<p>The program fast-tracks precision medicine research and was established through a $4 million gift from longtime UCSF supporters George and Judy Marcus. “We are really honored to be a part of this program,” says Bivona. “Creative funding like this is transforming innovation in medicine.”</p>
<h3>Projects Cover Breadth of Precision Medicine</h3>
<p>The program selected 12 projects encompassing 24 departments and 36 scientists across UCSF. The winning proposals cover the breadth of precision medicine and include projects analyzing genome-wide structural variations, testing the predictive potential of RNA, developing a novel approach to rheumatoid arthritis treatment, and personalizing lung cancer oncology, to name a few. </p>
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<p class="wysiwyg_quote--content">The Marcus’s generosity is spurring daring ideas and speeding their translation from the lab to patient care.</p>
<p class="wysiwyg_quote--author">Chancellor Sam Hawgood</p>
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<p>“The George and Judy Marcus Program is a pivotal institutional investment in precision medicine at UCSF. Precision Medicine is a field that is poised to transform health,” says Chancellor <a href="http://profiles.ucsf.edu/sam.hawgood" target="_blank">Sam Hawgood</a>, MBBS. “The Marcus’s generosity is spurring daring ideas and speeding their translation from the lab to patient care. Their visionary partnership is creating excitement across the university and accelerating our contributions to this important field.”</p>
<p>Precision medicine is an emerging approach to disease treatment and prevention using biological and biomedical data to develop personalized treatments and guide more precise, predictive and preventive medicine.</p>
<p>“Funding brave ideas and collaborative innovation in science and medicine is a priority for us,” says George Marcus. “UCSF is full of scientists thinking outside the usual framework. We are proud to be associated with pushing research to the next level.”</p>
<h3>Fast Pace of Projects</h3>
<p>The George and Judy Marcus Program funds research to improve patient outcomes and fosters high-risk, high-impact team science innovation. However, in contrast to other research funds, the Marcus Program is on an accelerated timeline. With an unusual fast track from application to funding, all projects must be able to yield discovery within the one-year funding period.</p>
<figure class="image image-2014_inline_2-col" style="float:left"><img alt="Trever Bivona" height="213" src="/sites/default/files/styles/2014_inline_2-col/public/fields/field_insert_file/news/Trever-Bivona2.jpg?itok=t-uD4BJN" width="170" /><figcaption>Trever Bivona, MD, PhD</figcaption></figure><p>“A very important and exciting aspect of this program is speed,” Bivona says. “Speed matters in scientific research when you have bold ideas and are forming compelling collaborations. You want the momentum, you want it early, and you want to sustain it. The quick process and launch of this program are really special.”</p>
<p>George Marcus is a member of the UCSF Foundation Board of Overseers and is a former UC Regent. He and his wife, Judy, developed the concept for the Marcus Program based on insights gathered during George’s years of service to the University and partnership with the chancellor. The couple also recently donated $1 million to support basic science PhD students through the George and Judy Marcus Discovery Fellowship Fund and $1 million to the Chancellor’s Annual Fund.</p>
<p>“Like the chancellor, we see personalized medicine as the future of health,” says George Marcus. “Encouraging team science at UCSF is an investment in that future.”</p>
<p>A complete list of the Marcus Program awardees is <a href="http://rdo.ucsf.edu/news/marcus-program-precision-medicine-innovation" target="_blank">available at the program's website</a>.</p>
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Wed, 27 Apr 2016 18:15:00 +0000mbillings402541 at https://www.ucsf.eduhttps://www.ucsf.edu/news/2016/04/402541/bold-innovation-program-fast-tracks-precision-medicine-research#commentsDavid Wofsy Receives American Rheumatology Association’s Highest Honorhttps://www.ucsf.edu/news/2015/11/224431/david-wofsy-receives-american-rheumatology-associations-highest-honor
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Mitzi Baker </div>
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<p>The highest honor of the American College of Rheumatology has been awarded to <a href="http://profiles.ucsf.edu/david.wofsy" target="_blank">David Wofsy</a>, MD, director of the <a href="http://www.russellenglemancenter.ucsf.edu/" target="_blank">Russell/Engleman Rheumatology Research Center</a> at UC San Francisco.</p>
<p>The <a href="http://www.rheumatology.org/Get-Involved/Awards/ACR-Awards" target="_blank">ACR’s Presidential Gold Medal </a>is given to recognize outstanding achievements spanning a rheumatologist’s entire career. The award was presented at the ACR annual meeting in San Francisco on Nov. 7.</p>
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<p>David Wofsy, MD</p>
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<p>Wofsy’s career traces a path that exemplifies translational science, first at the bench studying animal models for autoimmune diseases, and currently in the clinic conducting trials of novel biologic approaches to the treatment of people with systemic lupus erythematosus. Among his many research achievements, he was the first to report that targeting the signal for T-cells to activate could slow the progression of lupus in mice. This work laid the foundation for translational studies that resulted in FDA approval of abatacept, now used to treat rheumatoid arthritis and under investigation as a possible treatment for other autoimmune diseases.</p>
<p>“There is a revolution underway in the treatments available for patients with chronic inflammatory and autoimmune diseases,” says Wofsy. “When I entered training in rheumatology, our clinics were filled with disabled patients in wheelchairs and on gurneys. Those days are gone forever, but there is still a long way to go. It has been exciting and gratifying to play a small role in that progress.”</p>
<p>In addition to leading the Rheumatology Research Center, Wofsy also is the principal investigator of the National Institutes of Health-funded Autoimmunity Center of Excellence at UCSF as well as associate dean for Admissions in the UCSF School of Medicine.</p>
<p>“David’s leadership abilities are truly legendary,” wrote ACR past-president James O’Dell, MD, in Wofsy’s award nomination. “Several of my very favorite ACR memories were the rare occasions when someone would refer to something that I had done as ‘almost Wofsonian.’ In rheumatology leadership circles, there truly is no higher compliment.”</p>
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Mon, 16 Nov 2015 15:00:51 +0000louise.chu224431 at https://www.ucsf.eduhttps://www.ucsf.edu/news/2015/11/224431/david-wofsy-receives-american-rheumatology-associations-highest-honor#commentsEphraim Engleman, One of World’s Oldest Practicing Physicians, Dies at 104https://www.ucsf.edu/news/2015/09/131496/ephraim-engleman-one-worlds-oldest-practicing-physicians-dies-104
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<a href="/bio/louise-chu">Louise Chu</a> </div>
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<p>Ephraim Engleman (right), MD, shares a laugh with Jack Stobo, MD, executive vice president of UC Health, at a UCSF mentoring event in 2012. <em>Photo by Susan Merrell</em></p>
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<p><a href="http://profiles.ucsf.edu/ephraim.engleman" target="_blank">Ephraim Engleman</a>, MD, a pioneering rheumatologist whose passion and dedication to his work at UC San Francisco spanned a staggering seven decades, has died at 104.</p>
<p>Engleman passed away Wednesday doing what he loved so much: working as director of the <a href="http://www.russellenglemancenter.ucsf.edu/" target="_blank">Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center</a> at UCSF. One of the top arthritis research centers in the nation, it was renamed in honor of its founding director last year.</p>
<p>“Eph was a treasured member of the UCSF community,” said Chancellor <a href="http://profiles.ucsf.edu/sam.hawgood" target="_blank">Sam Hawgood</a>, MBBS. “Not only did he put UCSF on the map in arthritis research during his extraordinary career, he lived an incredibly rich and vibrant life that inspired his patients, his colleagues and countless others who had the pleasure of knowing him. He will be hugely missed.”</p>
<p>Lloyd “Holly” Smith, MD, former chair of the UCSF Department of Medicine and associate dean emeritus of the School of Medicine, noted that his colleague and friend lived “an exceptionally long and useful life” with a “deep capacity for friendship.”</p>
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<p><iframe align="right" frameborder="0" height="225" scrolling="no" src="//www.youtube.com/embed/W3dJbVWTii0" width="400"></iframe></p>
<p>Watch Ephraim Engleman share his 10 tips for longevity.</p>
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<p>The centenarian always addressed his senior status with good humor, often sharing his top 10 list of “commandments’’ for longevity. They include: avoid air travel, have lots of sex, keep breathing, and most appropriately, “Enjoy your work, whatever it is, or don't do it.”</p>
<p>In fact, Engleman declared that he never planned to retire. "I think retirement, generally speaking, is a great mistake," he <a href="http://www.sfgate.com/entertainment/article/Dr-Ephraim-Engleman-going-strong-at-age-100-2388946.php" target="_blank">told the <em>San Francisco Chronicle</em></a> as he turned 100 – spending his milestone birthday at the office.</p>
<p>Engleman celebrated birthday No. 102 in 2013 by releasing a memoir, <a href="http://www.amazon.com/My-Century-Ephraim-P-Engleman/dp/0615826075" target="_blank"><em>My Century</em></a>, which captured a fascinating life and career that almost didn’t turn toward medicine.</p>
<p>Born in San Jose in 1911, Engleman was a violin prodigy, performing concerts as early as 6 years old; and out of high school, he joined an orchestra that accompanied silent movies at the Fox California Theater. He was so busy working as a professional musician that it took him six years to earn his bachelor’s degree from Stanford and his grades, he admitted, were “terrible.”</p>
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<p>Engleman on his graduation day at Stanford. <em>Image courtesy of Engleman family</em></p>
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<p>Engleman and his wife, Jean, had been married since 1941. <em>Image courtesy of Engleman family</em></p>
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<p>Engleman still was accepted into Columbia’s medical school, where he began studying rheumatic disease, and followed with medical residencies at UCSF and Tufts University and a fellowship at Massachusetts General Hospital. During World War II, he served as a major and chief of the Army’s Rheumatic Fever Center.</p>
<p>In 1947, Engleman returned to UCSF, joining the clinical faculty and becoming the first rheumatologist to set up practice in San Francisco. He became a respected leader within the University, serving as president and co-founder of the Association of Clinical Faculty (1970-71), president of the Executive Medical Board of the UC Hospital and Clinics, San Francisco (1973-74), chief of Rheumatology at UCSF until 1982, and chief of the Arthritis Clinic until 1988.</p>
<p>Nationally his mark was just as indelible. In 1962-63, he was president of the American Rheumatism Association, now the American College of Rheumatology (1962-63); president of the National Society of Clinical Rheumatology (1967-69); and president of the International League Against Rheumatism (1981-85).</p>
<p>Engleman helped lead the field of rheumatology’s transformation over the years, from mostly prescribing aspirin and rest to wheelchair-bound patients in the 1950s, to the emergence of cortisone as a major treatment advance, to today’s biologics that work to interrupt immune system signals that are damaging joint tissue.</p>
<p>In the mid-1970s, Engleman led the National Commission on Arthritis, a task force charged with improving the woeful state of arthritis research. The subsequent National Arthritis Plan included the creation of what is now the National Institute of Arthritis, Musculoskeletal and Skin Diseases, and tripling of the ongoing federal budget for arthritis research.</p>
<p>He’s won many awards, including the Presidential Gold Medal Award by the American College of Rheumatology, the highest national honor in the field of rheumatology, and he’s authored more than 100 research papers.</p>
<p>In 1979, Congress gave $800,000 to establish the Rosalind Russell Rheumatology Research Center, named after the Hollywood star whose acting career largely ended because of severe rheumatoid arthritis and prompted her to become a crusader for arthritis research. Engleman was founding director of the center, helping raise more than $50 million in private support for rheumatology during his tenure.</p>
<p>The center is now a vital source of support for scientific investigation into the causes and potential cures of arthritis and autoimmune diseases and for training physicians and scientists to be the next generation of leaders in the field.</p>
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<p>Engleman (front left) with faculty and staff at the Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center at UCSF.</p>
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<p>“For those of us who have been part of the UCSF rheumatology program, there is no one who has had a greater impact on our work than Eph Engleman,” said <a href="http://profiles.ucsf.edu/lindsey.criswell" target="_blank">Lindsey Criswell</a>, MD, MPH, current chief of the UCSF Division of Rheumatology.</p>
<p>“Eph was a tireless supporter of the UCSF rheumatology program and never missed an opportunity to advocate for our faculty, trainees and the patients we cared for, “ she said. “He was particularly supportive of research, which he contributed to generously, both intellectually and financially.”</p>
<p>Throughout his distinguished career, Engleman has maintained his love for the violin, playing the instrument almost every night after dinner. He got together with friends each week to play chamber music as the San Andreas Quartet.</p>
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<p><img alt="" class="image-2014_inline_4-col" src="/sites/default/files/styles/2014_inline_4-col/public/fields/field_insert_file/news/engleman-dedication.jpg?itok=59zrdply" /></p>
<p>Engleman with his wife, Jean, at the dedication of the Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center at UCSF last year.</p>
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<p>Between work and music, it would have been tough to compete for Engleman’s affection, but his greatest love was his family. He called his wife of 74 years, Jean Sinton Engleman, his biggest inspiration.</p>
<p>A father of three, he’s seen his two sons, E. Philip Engleman and Edgar G. Engleman, also become doctors, as did one of his grandchildren. E. Philip Engleman, a Kaiser Permanente pathologist, actually retired several years ago “against my advice,” the elder Engleman had said.</p>
<p>Edgar Engleman, a pathologist and director of the Stanford Blood Center, called his father, "an incredible role model."</p>
<p>"He was so positive and optimistic. He was a born leader and genuinely a joy to be around," he said.</p>
<p>Engleman is survived by his wife, his two sons, daughter Jill Roost, six grandchildren and three great-grandchildren.</p>
<p>“It's been a wonderful marriage and we have wonderful children who have been successful, I have been successful – all of which contributes to a happy marriage,” he <a href="http://www.huffingtonpost.com/lily-sarafan/ephraim-engleman_b_2806506.html" target="_blank">told the <em>Huffington Post</em></a> in 2013. “I do feel that a happy marriage and a happy family are important factors that contribute to longevity.”</p>
<p><strong><em>For more campus news and resources, visit <a href="http://www.ucsf.edu/pulse">Pulse of UCSF</a>.</em></strong></p> </div>
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Fri, 04 Sep 2015 19:50:00 +0000louise.chu131496 at https://www.ucsf.eduhttps://www.ucsf.edu/news/2015/09/131496/ephraim-engleman-one-worlds-oldest-practicing-physicians-dies-104#commentsChildhood Syndrome Combining Lung Disease, Arthritis Is Identifiedhttps://www.ucsf.edu/news/2015/04/125231/childhood-syndrome-combining-lung-disease-arthritis-identified
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Discovery Suggests Mechanism, Possible Therapies for Severe Disorder </h2>
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<p>Using the latest genome sequencing techniques, a research team led by scientists from UC San Francisco, Baylor College of Medicine, and Texas Children’s Hospital has identified a new autoimmune syndrome characterized by a combination of severe lung disease and arthritis that currently has no therapy.</p>
<p>The hereditary disorder, which appears in early childhood, had never been diagnosed as a single syndrome. The new research revealed that it is caused by mutations in a single gene that disrupt how proteins are shuttled around within cells. Patients with the newly discovered syndrome have a poor prognosis, and at present can only be treated with anti-inflammatory and immunosuppressant drugs. Many have lung disease so severe that they must receive lung transplants.</p>
<p>Thanks to biological mechanisms revealed in the research, patients could soon have access to a wider range of therapies, according to <a href="http://profiles.ucsf.edu/anthony.shum">Anthony K. Shum</a>, MD, UCSF assistant professor of medicine and co-senior author of the new study. “We believe that there are small molecules in development that can help correctly traffic the proteins that are misdirected in this syndrome, so that’s something we really want to go after.”</p>
<p>Levi B. Watkin, PhD, a postdoctoral fellow at Baylor, former UCSF postdoctoral fellow Birthe Jessen, PhD, and Wojciech Wiszniewski, MD, assistant professor of molecular and human genetics at Baylor, led the research, which is reported in the April 2011, 2015 online edition of <em>Nature Genetics</em>.</p>
<p>For Shum, the project was sparked when a woman was admitted to the Emergency Department at a California medical center with pulmonary hemorrhage. In the course of treating the patient, Shum learned that she had arthritis as well, and that a sibling and aunt also had both lung disease and arthritis.</p>
<p>Some time later, when Shum encountered the patient’s mother in the hospital's corridor, she mentioned that a distant cousin she had never met had posted on a social media site that her own two-and-a-half-year-old daughter was being treated at another hospital for pulmonary hemorrhage. Shum went to that hospital and found that, in addition to dramatic hemorrhaging in the child’s lungs, she too had arthritis.</p>
<p>With the help of UCSF medical students, Shum began searching for other affected family members and ultimately identified a distant relative in another state with the same syndrome. The group then sequenced DNA samples from nine family members, some with the syndrome and some who are unaffected, to search for mutations that might underlie the disorder. “We sort of took a flyer,” Shum said. “The likelihood of finding something was low.”</p>
<p>UCSF scientists quickly zeroed in on a region of the genome containing a gene known as <em>COPA, </em>a result in which they initially had little confidence. “<em>COPA</em> mutations were completely unexpected,” Shum said. “The COPA protein is expressed throughout the body, and no diseases associated with this gene had ever been reported.” But an independent genetic analysis produced the same result: using this second method, Shum said, “You’ll usually see peaks spread across the genome, but we only got a single peak. It was highly significant, and <em>COPA</em> was right under it.”</p>
<p>The COPA protein is essential in intracellular transport – the process by which newly made proteins are moved to their proper locations in the cell – and the scientists found that the <em>COPA </em>mutations seen in the patients “cripple the protein,” said Shum, preventing it from performing this vital function.</p>
<p>Encouraged by the consistency and clarity of these results, Shum reached out to physicians at other institutions to see if they had seen patients with the same cluster of symptoms.</p>
<p>“By pure serendipity,” Shum said, he was soon contacted by co-senior author Jordan S. Orange, MD, PhD, director of the Texas Children’s Hospital Center for Human Immunobiology, who had seen similar cases. Moreover, Orange’s colleague, sequencing expert James R. Lupski, MD, PhD, co-senior author and Cullen Professor of Molecular and Human Genetics at Baylor, had independently fingered <em>COPA </em>mutations in his own genomic analyses of these cases.</p>
<p>Ultimately the UCSF-Baylor-Texas Children’s team identified five families in which 30 family members carried deleterious <em>COPA</em> mutations. Only 21 of those carriers were affected by lung and joint problems, suggesting that, although the disease is inherited, it has “incomplete penetrance” – the presence of <em>COPA</em> mutations does not solely determine that an individual will develop the syndrome.</p>
<p>“The fact that we discovered five unrelated families and over 20 affected individuals in just over two and half years of investigating this leads me to believe that this is by no means ultra-rare,” said Orange.</p>
<p>Subsequent experiments with tissue from affected patients revealed that faulty protein trafficking by mutant <em>COPA</em> results in a condition known as “cellular stress,” which in turn sets off an autoimmune reaction mediated by immune-system cells known at Th17 cells.</p>
<p>Because Th17 cells have already implicated in autoimmune diseases, particularly in rheumatoid arthritis, Shum believes that targeting these cells with drugs may provide a new therapeutic avenue for those with the syndrome. “In our current research we’re making sure that we have a clear mechanism, so we can come up with a potential drug target,” he said.</p>
<p>Orange added that the new research may have ramifications that extend beyond this particular syndrome, especially for arthritis therapies. “We are excited to learn how variants of this disease might be more broadly applicable and might be instructive to our overall understanding of arthritis,” he said.</p>
<p>In the meantime, Shum said, patients and their families have been gratified that the mysterious condition affecting their families is beginning to be understood. “When I first contacted the families we located, it was a huge relief to them to know that there are other people like them and that someone is working on this disorder.”</p>
<p>The research was funded by the National Institutes of Health, The Jeffrey Modell Foundation, The Foundation of the American Thoracic Society, The Pulmonary Fibrosis Foundation, and The Nina Ireland Program for Lung Health at UCSF.</p>
<p>UCSF is the nation's leading university exclusively focused on health. Now celebrating the 150th anniversary of its founding as a medical college, UCSF is dedicated to transforming health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with world-renowned programs in the biological sciences, a preeminent biomedical research enterprise and top-tier hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals.</p>
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Mon, 20 Apr 2015 15:00:00 +0000melanie.williams125231 at https://www.ucsf.eduhttps://www.ucsf.edu/news/2015/04/125231/childhood-syndrome-combining-lung-disease-arthritis-identified#commentsIn Autoimmune Diseases Affecting Millions, Researchers Pinpoint Genetic Risks, Cellular Culpritshttps://www.ucsf.edu/news/2014/10/120121/autoimmune-diseases-affecting-millions-researchers-pinpoint-genetic-risks
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<a href="/bio/jeffrey-norris">Jeffrey Norris</a> </div>
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New Software Tool Helps Makes Sense of Previous Genetic Data on Multiple Sclerosis, Type 1 Diabetes, Other Diseases </h2>
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<p>Scores of autoimmune diseases afflicting one in 12 Americans — ranging from type 1 diabetes, to multiple sclerosis (MS), to rheumatoid arthritis, to asthma — mysteriously cause the immune system to harm tissues within our own bodies. Now, a new study pinpoints the complex genetic origins for many of these diseases, a discovery that may lead to better diagnosis and ultimately to improved treatments.</p>
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<p><img alt="Alex Marson, MD, PhD" class="image-2014_inline_2-col" src="/sites/default/files/styles/2014_inline_2-col/public/fields/field_insert_file/news/AM01%20mug.jpeg?itok=POs9OdHZ" style="height:223px; width:170px" /></p>
<p>Alex Marson, MD, PhD</p>
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<p>A team of scientists from UC San Francisco, the Broad Institute of MIT and Harvard, and Yale School of Medicine developed a new mathematical tool to more deeply probe existing DNA databases. In so doing they discovered how certain DNA variations, when inherited, are likely to contribute to disease.</p>
<p>By applying their method to analyzing data from previous studies of 21 different autoimmune diseases, the research team has deepened scientific understanding of the genetic underpinnings of a wide range of these disorders. They also found the specific immune cells most responsible for the diseases. Their study is published online on October 29, 2014 in <em>Nature.</em></p>
<p>The researchers examined a wealth of data from 39 large-scale studies called genome-wide association studies (GWAS). Teams of scientists in recent years have conducted GWAS — typically enlisting thousands of study participants — to identify large blocks of DNA within the human genome within which genetic variants are implicated as risk factors for common diseases. But examination of GWAS data to date has seldom pointed to altered proteins, as surprisingly few protein-encoding gene variants within these broad swaths of DNA have been associated with the diseases under investigation.</p>
<p>Instead, the genetic risks identified through GWAS more often appear to be associated with DNA variations that do not reside within genes. The nature of this risk has defied understanding until now, fueling a perception that few medical benefits have thus far emerged from large-scale studies of human genetic variation being conducted in the wake of the initial Human Genome Project.</p>
<p>In the new study the researchers found that the presence of specific genetic variants in different autoimmune diseases can alter patterns of activity of genes in particular ways that affect functions of the immune system. This was true despite the fact that the genetic variants are not within genes.</p>
<p>To make their discoveries, the researchers developed software and used next-generation sequencing techniques to probe “epigenetic” characteristics of specialized immune cells, in which gene activity is affected without changes to the DNA sequence itself within the affected genes.</p>
<p>The team discovered that a majority of key DNA changes associated with autoimmune diseases occur in functional bits of DNA known as “enhancers.”</p>
<p>Although DNA exists within cells as long, stringy molecules, DNA can bend back upon itself with the support of the chromosome’s structural proteins, so that one piece of DNA may interact with another. Enhancers fold in this way to bind to DNA switches that turn genes on. In general the enhancers identified in the <em>Nature</em> study as playing a role in autoimmune disease were DNA sequences that did not match DNA-sequence motifs previously thought to be essential to enhancers, and had not previously been seen as having any functional role.</p>
<p>“Once again, research is revealing new meaning in the world of DNA once thought of as junk — short, seemingly random DNA sequences that in fact serve meaningful roles in human physiology,” said <a href="http://profiles.ucsf.edu/alexander.marson">Alex Marson</a>, MD, PhD, UCSF Sandler Faculty Fellow and the corresponding author for the study.</p>
<p>By painstakingly mapping enhancers in specialized immune cells, and by tracking down patterns of altered gene activation that resulted from the presence of variants found in GWAS studies, the researchers identified patterns of activity within the genome and cell types associated with the autoimmune diseases. Many autoimmune diseases were associated with immune cells known as T helpers. The authors suggest that genetic variation may be tuning the response of these key immune cells to stimuli within their surroundings to increase the risk of autoimmunity.</p>
<p>Marson initiated the scientific collaboration while he was an MD/PhD student at Harvard and MIT and a medical resident at the Brigham and Women’s Hospital, joining together with the senior scientists for the study: Bradley Bernstein, MD, PhD, associate member of Broad Institute and professor of pathology at Harvard, and David A. Hafler, MD, professor of neurology and immunobiology, and chair of the Department of Neurology at Yale. Marson and Kyle Kai-How Farh, MD, PhD, a clinical geneticist and postdoctoral fellow with the Broad Institute, are co-first authors of the <em>Nature</em> article.</p>
<p>Among other revelations, the new study strongly links the cause of MS to the immune system, not to genetic variants associated with the nervous system. According to Hafler, the results provide definitive evidence that MS is an autoimmune disease, and that the immune system plays the primary role. “This is highly consistent with the new multiple sclerosis treatments that work on the immune system, suggesting that we finally have a good handle as to the underlying causes of MS,” Hafler said.</p>
<p>The new ability to associate specific genetic variants on one hand with cell circuits that control gene activity and alter the physiology of specific immune cell types on the other will enable medical researchers to more precisely target therapeutic interventions in autoimmune diseases in order to dampen aberrantly fired-up immune responses, according to Marson.</p>
<p>In his UCSF lab, Marson intends to probe more deeply how these newly identified DNA variants in enhancers affect cells, and how their disease-causing effects might be mitigated by DNA manipulations carried out using gene-editing technologies known as CRISPR.</p>
<p>The National Institutes of Health and the National Multiple Sclerosis Society provided major funding for the study.</p>
<p>UCSF is the nation's leading university exclusively focused on health. Now celebrating the 150th anniversary of its founding as a medical college, UCSF is dedicated to transforming health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with world-renowned programs in the biological sciences, a preeminent biomedical research enterprise and top-tier hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals.</p>
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Wed, 29 Oct 2014 18:00:00 +0000melanie.williams120121 at https://www.ucsf.eduhttps://www.ucsf.edu/news/2014/10/120121/autoimmune-diseases-affecting-millions-researchers-pinpoint-genetic-risks#commentsAutoimmune Diseases May Succumb to New Drug Strategyhttps://www.ucsf.edu/news/2014/04/113961/autoimmune-diseases-may-succumb-new-drug-strategy
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<a href="/bio/jeffrey-norris">Jeffrey Norris</a> </div>
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UCSF/Harvard Genome Study Identifies Three Possible Drug Candidates for Multiple Diseases </h2>
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<p>New pharmaceuticals to fight autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and psoriasis, may be identified more effectively by adding genome analysis to standard drug screening, according to a new study by a research team led by UC San Francisco and Harvard researchers, in collaboration with Tempero and GlaxoSmithKlein.</p>
<p>In a study reported online April 17, 2014 in the journal <a href="http://www.sciencedirect.com/science/article/pii/S1074761314001186"><em>Immunity</em></a>, the scientists combined drug screening with state-of-the-art techniques for analyzing the genome, leading to three small molecules that improved symptoms in a mouse form of multiple sclerosis.</p>
<p>The three potential drug candidates, selected from a large library of screened chemicals, each knocked down the response of Th17 cells, a type of immune cell that drives many autoimmune diseases by attacking normal cells in the body. More specifically, the drugs homed in on an essential molecule within the Th17 cells.</p>
<p>“We examined what makes Th17 cells – which play a crucial role in multiple autoimmune diseases – distinct from other closely related T cells within the immune system,” said <a href="http://profiles.ucsf.edu/alexander.marson">Alexander Marson</a>, MD, PhD, a leading T cell expert and member of the UCSF Diabetes Center. “Then we investigated several small molecules that inhibit the development and function of these cells. When the Th17 cells were hit by these molecules we saw less severe multiple-sclerosis-like symptoms in the mice.”</p>
<p>The research team, led by Marson and Vijay K. Kuchroo, PhD, an immunologist at Brigham and Women’s Hospital in Boston and Harvard Medical School, combined powerful techniques to shed light on a class of protein molecules within cells known as transcription factors.</p>
<p>Drug designers have rarely targeted transcription factors. Each transcription factor binds to DNA at a unique set of locations along the 23 pairs of chromosomes, and thereby influences which genes are turned on and off to trigger the protein production that drives cell development and function.</p>
<p>Different transcription factors shape the development of different types of T cells within the immune system, Marson and others are discovering. In their new study, Marson found that the transcription factor called ROR gamma t has a unique role in guiding development of Th17 cells, while inhibiting the development of other immune cells.</p>
<p>Preventing Th17 cells from developing by inhibiting the function of ROR gamma t appears to be an effective strategy for fighting autoimmune diseases, Marson said.</p>
<p>“There already are drugs in clinical trials for autoimmune diseases – including psoriasis and rheumatoid arthritis – that are antibodies for IL-17 or IL-17 receptors,” Marson said, referring to signaling molecules secreted by Th17 cells that can help trigger an attack our own healthy tissue, and the receptors that receive those signals. “This is an entirely different and promising approach to fight autoimmune disease," he said.</p>
<p>“Our studies map a path to targeting transcription factors and provide both insight into how transcriptional regulators shape the identity and affect the development of Th17 cells, and also into how different drug molecules might affect these regulatory circuits in the cells,” he said.</p>
<p>To reveal the distinct and sometimes subtle effects of the drug candidates, the researchers studied the entire genome to see where ROR gamma t attached to DNA, which genes were activated or turned off as a result, and how these effects were altered by the drug candidates.</p>
<p>“Not only did we look at which genes are turned on and off, but we also systematically looked at DNA-binding sites across this genome,” Marson said. “This pushes the boundary of what’s typically done.”</p>
<p>In addition to attaching to DNA, ROR gamma t has a pocket that looks like it should bind a hormone, Marson said. But what this hormone might be, and its effects, are unknown. The different drug candidates that inhibited Th17 development had different effects on ROR gamma t and resultant DNA binding and gene activation, possibly because of distinct interactions with the hormone-binding pocket, Marson said.</p>
<p>Analyzing the large data sets generated through such experiments could help pharmaceutical companies wading into development of drugs that target transcription factors to test the waters, Marson said, enabling drug developers to better understand mechanisms of drug action and to more easily see gene activity that could trigger side effects.</p>
<p>According to Marson, “This is a new, broadly applicable approach for systematically evaluating leading drug candidates for autoimmune diseases.”</p>
<p>The National Multiple Sclerosis Society and the National Institutes of Health provided major funding for the research.</p>
<p>UCSF is the nation’s leading university exclusively focused on health. Now celebrating the 150th anniversary of its founding as a medical college, UCSF is dedicated to transforming health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with world-renowned programs in the biological sciences, a preeminent biomedical research enterprise and two top-tier hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital San Francisco. Please visit <a href="http://www.ucsf.edu">www.ucsf.edu</a>.</p>
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Wed, 30 Apr 2014 18:49:00 +0000melanie.williams113961 at https://www.ucsf.eduhttps://www.ucsf.edu/news/2014/04/113961/autoimmune-diseases-may-succumb-new-drug-strategy#commentsStanford, UCSF Flexing Muscles Against Arthritishttps://www.ucsf.edu/node/108511
External URL:&nbsp;
<a href="http://www.sfgate.com/health/article/Stanford-UCSF-flexing-muscles-against-arthritis-4765795.php#photo-5099525" target="_blank">http://www.sfgate.com/health/article/Stanford-UCSF-flexing-muscles-against-arthritis-4765795.php#photo-5099525</a>
Source:&nbsp;
San Francisco Chronicle
Topics:&nbsp;
<a href="/topics/arthritis" typeof="skos:Concept" property="rdfs:label skos:prefLabel" datatype="">Arthritis</a> Thu, 29 Aug 2013 00:19:29 +0000ddeike108511 at https://www.ucsf.eduGold Therapy for Rheumatoid Arthritishttps://www.ucsf.edu/node/107871
External URL:&nbsp;
<a href="http://www.everydayhealth.com/rheumatoid-arthritis/gold-therapy-for-rheumatoid-arthritis.aspx" target="_blank">http://www.everydayhealth.com/rheumatoid-arthritis/gold-therapy-for-rheumatoid-arthritis.aspx</a>
Source:&nbsp;
Everyday Health
Topics:&nbsp;
<a href="/topics/arthritis" typeof="skos:Concept" property="rdfs:label skos:prefLabel" datatype="">Arthritis</a> Mon, 15 Jul 2013 10:01:00 +0000ddeike107871 at https://www.ucsf.edu